Department of Dermatology, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan

Transcription

1 Case Reports An ATP2A2 Missense Mutation in a Japanese Family with Darier Disease: A Case Report and Review of the Japanese Darier Disease Patients with ATP2A2 Mutations Min Li, Naoyuki Higashi, Hajime Nakano and Hidehisa Saeki 1 Department of Dermatology, Nippon Medical School Tama Nagayama Hospital, Tokyo, Japan 2 Department of Dermatology, Hirosaki University Graduate School of Medicine, Aomori, Japan 3 Department of Dermatology, Nippon Medical School Hospital, Tokyo, Japan Darier disease (DD) is a rare autosomal dominant skin disorder due to mutations in the ATP2A2 gene, which encodes sarco/endoplasmic reticulum Ca 2+ ATPase isoform 2 (SERCA2). The clinical manifestations of DD are characterized by warty papules and plaques in seborrheic areas, and association with neuropsychiatric abnormalities has also been reported in a few families with DD. We herein report a classic Japanese DD case with a previously described mutation (p.c560r) in ATP2A2. InJapan, 26mu- tations in the ATP2A2 gene in 7 pedigrees and 19 sporadic cases with DD have been reported, among which one pedigree and one sporadic case were accompanied by neuropsychiatric symptoms. A review of the reports confirmed that most mutations were of the missense type and no consistent genotypephenotype correlations were found. (J Nippon Med Sch 2017; 84: ) Key words: Darier disease, ATP2A2 mutation Introduction Darier disease (DD), first described by Darier and White in 1889, is a rare autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp and forehead) 1. Other clinical features include palmo-plantar pits, nail changes, and association with neuropsychiatric abnormalities such as mild mental retardation and epilepsy has also been reported in a few families with DD 1. The penetration of the disease is complete and the age of onset is typically within the second decade. Mutations in the ATP2A2 gene are the cause of DD 2. This gene is located on chromosome 12q and encodes the sarco/endoplasmic reticulum Ca 2+ ATPase isoform 2 (SERCA2), a calcium pump transporting Ca 2+ from the cytoplasm into the ER lumen 2. Herein, we report a typical Japanese DD patient with a mutation in ATP2A2 that has been previously described and review the reported Japanese DD cases with ATP2A2 mutations. Case A 34-year-old woman presented with a severe pruritic skin eruption on her neck and trunk. Her skin lesions, diagnosed as folliculitis, were mild 10 years ago, but became exacerbated 1 year ago after catching a cold. Physical examination revealed multiple slightly crusted brownish-red keratotic papules and plaques on the neck and trunk (Fig. 1A and B). Nail lesions with V-shaped notches on the distal end of the nail plate were also seen (Fig. 1C). She had no history of neuropsychiatric abnormalities. A skin biopsy taken from her back revealed suprabasal acantholysis in the epidermis with dyskeratotic cells (known as corps ronds and grains) (Fig. 2A and B). These clinical and histological findings were consistent with the diagnosis of DD. After obtaining informed consent, genomic DNA was extracted from the peripheral blood leukocytes and all 21 exons of the ATP2A2 gene, including intron-exon boundaries, were amplified by polymerase chain reaction as described previously 3. Direct sequencing revealed a heterozygous missense mutation in exon 13, c.1678t>c, resulting in the amino acid Correspondence to Min Li, MD, Department of Dermatology, Nippon Medical School Tama Nagayama Hospital, Nagayama, Tama, Tokyo , Japan limin@nms.ac.jp Journal Website ( 246 J Nippon Med Sch 2017; 84 (5)

2 ATP2A2 Mutation in Darier Disease C A B Fig. 1 (A) Multiple slightly crusted brownish-red keratotic papules scattered and coalesced to form verrucous plaques on the back, (B) chest and abdomen. (C) V-shaped notches on the distal end of the nail plate. A 560 c.1678t>c pa nt C B 560 Normal D Fig. 2 (A) Histological findings showed focal hyperkeratosis, parakeratosis in the epidermis and suprabasal acantholytic cleft formation. (B) Dyskeratosis with corps ronds (arrow) and grains (arrowhead). (haematoxylin-eosin, original magnification A 100, B 200). (C) Sequence analysis of the ATP2A2 gene revealed a nucleotide transition of T to C (1678T>C) in one allele of exon 13, resulting in the amino acid change from cysteine to arginine (C560R) indicated by the arrow. (D) Wild-type sequence of exon 13. change from cysteine to arginine (p. C560R ) (Fig. 2C and D). DD generally responds well to oral retinoids, however we did not choose this treatment due to its teratogenic side effects. Treatment with an oral antihistamine, minocycline (200 mg/day), topical corticosteroids, active vitamin D3 ointment and heparinoid emollients relieved her symptoms over several months with mild residual hyperpigmentation. During one year and a half following up, her symptoms relapsed two times due to catching a cold and stopping treatment by herself. The same mutation was also detected in her affected J Nippon Med Sch 2017; 84 (5) 247

3 M. Li, et al Table 1 ATP2A2 mutations and clinical features of Japanese patients with DD reported previously Case number Patient age, sex (onset age, y) Family history Location, Mutation Amino acid change Consequence Protein domain Clinical Severity 6 Features Reference (year of publish) F (10y) Exon 14, c.1839c>a C613X nonsense moderate 10 (2001) 70F (20y) + Exon 8, c.961c>t L321F missense Stalk 4 severe 65M (30y) Exon 8, c.820a>g I274V missense M3 mild 76M (50y) Exon 15, c.2157 G>A M719I missense Hinge domain moderate 5 8 ND Exon 7, c.547c>a E183K missense Β-strand ND 11 (2003) Exon 14, c.2039c>t P680 L missense Hinge domain Exon 7, c.548a>t E183V missense Β-strand Exon 7, Ctgt ctcatgt 553insCAT 185insH Β-strand M (30y)/50M (10y) + Exon 8, c.697 G>C G233R missense Β-strand mild/severe 12 (2004) 17F (4y)/13F (12y) + Exon 8, c.952t>c C318R missense Stalk 4 severe/mild 54F/33F/28F (all 10y) + Exon 16, c.2512 G>C A838P missense M7 severe 40M Exon 1, c.1a>g M1V missense Start codon severe 13F (11y) Exon 1, c.115a>g N39D missense Upstream stalk moderate 33F (31y) Exon 6, c.539t>g L180R missense Β-strand moderate 48M (44y) Exon 15, TGC TGGC 2170insG frameshift insertion Hinge domain moderate 16 34F (13y) + Exon 15, c.2300a>g N767S missense M5 haemorrhagic variant 13 (2007) 17 20M (11y) Exon 17, c.2541delc deletion M7 moderate 14 (2009) 18 22M (10y) Exon 2, c.120_122delgtt p.leu41del deletion Stalk 1 comedonal type 15 (2010) 19 48M (20y) + Exon 15, c.2224 G>A G742R missense Stalk 5 moderate 16 (2012) 20 80M (75y) Exon 14, c.2092 G>C A698P missense ATP-binding domain mild 8 (2013) 21 67M (47y) Exon 8, c.1043t>c I348T missense Phosphorylation severe 17 (2013) 22 38F (33y) Intron 10, c G>T splice site Phosphorylation moderate 18 (2014) 23 40F Exon 18, c.2721a>c E907D missense M8 moderate 19 (2015) 24 46F (20y) Intron 1, c.119-2a>t splice site Stalk 1 moderate 20 (2015) 25 41F + Intron 10, c a>g splice site Phosphorylation ND (bipolar disorder) 4 (2016) 26 66M (65y) Exon 8, c.953 G>A C318T missense Stalk 4 moderate (schizophrenia) 21 (2016) This 34F (24y) + Exon 13, c.1678t>c C560R missense ATP-binding domain moderate study M, transmembrane domain; ND, no data 248 J Nippon Med Sch 2017; 84 (5)

4 ATP2A2 Mutation in Darier Disease father who showed mild phenotype, which pathologically confirmed the diagnosis of DD combined with lichen amyloidosis (data not shown). Discussion More than 248 ATP2A2 mutations have now been reported in DD patients 4. The mutations, including missense, nonsense, frame-shift or inframe insertion/deletion and splice-site mutations are spread throughout the ATP2A2 gene without hot spots and most are familyspecific 3,5,6. Ringpfeil et al. 6 noted that 15 of 92 mutations have been reported more than once, in which 12 were identified in two unrelated individuals/families. No consistent genotype-phenotype correlations have been established 3,6. There are considerable inter/intrafamilial variations in DD, which suggests that additional modifying genes and/or environmental factors influence the phenotype 3,6. ATP2A2 mutations cause the dominant DD phenotype through haploinsufficiency 2. The mutation C560R, located in the ATP-binding domain, decreases the protein expression of SERCA2 4.The change from a hydrophobic amino acid into a basic one, a non-conservative amino acid change, alters the charge, polarity, hydrophobicity and size of the amino acid residue, and likely interferes with SERCA2 function 3. Jacobsen et al. 7 reported the same mutation in a sporadic DD with schizoid personality psychosis and a pedigree with bipolar disorder and they suggested that mutations in the ATP-binding domain might have relevance in mood disorders. But in our case and another mild phenotype Japanese DD case 8 with mutation in the ATPbinding domain (A698P), no neuropsychiatric symptoms were found. Three pedigrees with nonsense or frameshift insertion/deletion mutations in the ATP-binding domain, were mild/moderate, and two of them had neuropsychiatric symptoms 3. Neuropsychiatric abnormalities did not seem to be associated with the types of ATP2A2 mutations 9. The association between DD and neuropsychiatric abnormalities may be a pleiotropic effect of ATP2A2 mutations on both the skin and brain 4,7. In Japan, 26 mutations in the ATP2A2 gene in 7 pedigrees and 19 sporadic cases with DD have been reported 4,8, The genetic and clinical features of Japanese DD patients are summarized in Table 1. There were no hot spot mutations and most mutations were of the missense type (18 of 26 mutations, 69%). P680L, C318R, A838P, M1V, N39D, N767S, I348T have been reported previously. C318R, occurring in stalk 4, exhibited a severe erosive phenotype 3. C318R and G233R 12, A838P and M1V 9 had phenotypic variations within families. N39D and I348T were identified in moderate DD with depression or behavioral problems 6. Mutations with severe phenotype affected the cytoplasmic stalk, transduction, phosphorylation and transmembrane domains M6/M7 6. N767S, the most frequently reported mutation in DD, has been reported 11 times 5. This mutation was associated with an acral haemorrhagic variant of DD or neuropsychiatric abnormalities in some cases, but without these features in others 5, and the acral haemorrhagic variant of DD might also be caused by mutation C268F in M3 9.Wadaetal. 22 reported a case of segmental DD with I54V found only in the affected skin, but not in the peripheral leucocytes, which represented genetic mosaicism resulting from postzygotic mutations in the ATP2A2 gene. In these reported Japanese DD cases, one pedigree and one sporadic case had neuropsychiatric symptoms. In summary, our review of Japanese DD with mutations confirms that most mutations were of the missense type; no consistent genotype-phenotype correlations were found. Conflict of Interest: The authors declare no conflict of interest. References 1 Burge SM, Wilkinson JD: Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol 1992; 27: Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S, Smith M, Munro CS, O Donovan MC, Craddock N, Kucherlapati R, Rees JL, Owen M, Lathrop GM, Monaco AP, Strachan T, Hovnanian A: Mutations in ATP2A2, encoding a Ca 2+ pump, cause Darier disease. Nat Genet 1999; 21: Sakuntabhai A, Burge S, Monk S, Hovnanian A: Spectrum of novel ATP2A2 mutations in patients with Darier`s disease. Human Molecular Genetics 1999; 8: Nakamura T, Kazuno A, Nakajima K, Kusumi I, Tsuboi T, Kato T: Loss of function mutations in ATP2A2 and psychoses: A case report and literature survey. Psychiatry Clin Neurosci 2016; 70: Green EK, Gordon-Smith K, Burge SM, Grozeva D, Munro CS, Tavadia S, Jones L, Craddock N: Noval ATP2A2 mutations in a large sample of individuals with Darier disease. J Dermatol 2013; 40: Ringpfeil F, Raus A, DiGiovanna JJ, Korge B, Harth W, Mazzanti C, Uitto J, Bale SJ, Richard G: Darier diseasenovel mutations in ATP2A2 and genotype-phenotype correlation. Exp Dermatol 2001; 10: Jacobsen NJ, Lyons I, Hoogendoorn B, Burge S, Kwork PY, O Donovan MC, Craddock N, Owen MJ: ATP2A2 mutations in Darier s disease and their relationship to neuropsychiatric phenotypes. Hum Mol Genet 1999; 8: Ueno D, Hamada T, Hashimoto T, Hatano Y, Okamoto O, Fujiwara S: Late-onset Darier s disease due to a novel missense mutation in the ATP2A2 gene: A different mis- J Nippon Med Sch 2017; 84 (5) 249

5 M. Li, et al sense mutation affecting the same codon has been previously reported in acrokeratosis verruciformis. J Dermatol 2013; 40: Ruiz-Perez VL, Carter SA, Healy E, Todd C, Rees JL, Steijlen PM, Carmichael AJ, Lewis HM, Hohl D, Itin P, Vahlquist A, Gobello T, Massanti C, Reggazini R, nagy G, Munro CS, Strachan T: ATP2A2 mutations in Darier s disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class. Hum Mol Genet 1999; 8: Takahashi H, Atsuta Y, Sato K, Ishida-Yamamoto A, Suzuki H, Iizuka H: Novel mutations of ATP2A2 gene in Japanese patients of Darier s disease. J Dermatol Sci 2001; 26: Ikeda S, Mayuzumi N, Shigihara T, Epstein EH Jr, Goldsmith LA, Ogawa H: Mutations in ATP2A2 in patients with Darier s disease. J Invest Dermatol 2003; 121: Onozuka T, Sawamura D, Yokota K, Shimizu H: Mutational analysis of the ATP2A2 gene in two Darier disease families with intrafamilial variability. Br J Dermatol 2004; 150: Hamata T, Yasumoto S, Karashima T, Ishii N, Shimada H, Kawano Y, Imayama S, McGrath JA, Hashimoto T: Recurrent p.n767s mutation in the ATP2A2 gene in a Japanese family with haemorrhagic Darier disease clinically mimicking epidermolysis bullosa simplex with mottled pigmentation. Br J Dermatol 2007; 157: Hamata T, Ishii N, Fukuda S, Takagi A, Yasumoto S, Ikeda S, Hashimoto T: A new c.2541delc mutation in the ATP2A2 gene in a Japanese patient with Darier s disease. J Eur Acad Dermatol Venereol 2009; 23: Tsuruta D, Akiyama M, Ishida-Yamamoto A, Imanishi H, Mizuno N, Sowa J, Kobayashi H, Ishii M, Kurokawa I, Shimizu H: Three-base deletion mutation c delgtt in ATP2A2 leads to the unique phenotype of comedonal Darier diease. Br J Dermatol 2010; 162: Miyabe C, Mitsuhashi Y, Saito M, Tsuboi R: Novel mutation in the ATP2A2 gene in a Japanese patient with extremely hyperkeratotic lesions. J Dermatol 2012; 39: Oizumi A, Haruna K, Negi O, Kimura U, Hamata T, Hashimoto T, Suga Y: A case of Darier disease with erythroderma caused by infection. Rinsho derma 2013; 55: (in Japanese). 18 Yoneda K, Demitsu T, Kubota Y: Novel ATP2A2 mutation in a patient with Darier s disease. J Dermatol 2014; 41: Kaibuchi-Noda K, Sugiura K, Takeichi T, Miura S, Kagami S, Takama H, Hino H, Akiyama M: Darier s Disease: A novel ATP2A2 missense mutation at one of the calcium-binding residues. Acta Derm Venereol 2015; 95: Akagi A, Kitoh A, Shimomura Y, Miyachi Y, Kabashima K: Novel mutation of the ATP2A2 gene in a case of Darier s disease featuring erosive lesions. Eur J Dermatol 2015; 25: Takeichi T, Sugiura K, Nakamura Y, Fujio Y, Konohana I, Akiyama M: Darier s disease complicated by Schizophrenia caused by a novel ATP2A2 mutation. Acta Derm Venereol 2016; 96: Wada T, Shirakata Y, Takahashi H, Murakami S, Iizuka H, Suzuki H, Hashimoto K: A Japanese case of segmental Darier s disease caused by mosaicism for the ATP2A2 mutation. Br J Dermatol 2003; 149: (Received, May 31, 2017) (Accepted, August 1, 2017) 250 J Nippon Med Sch 2017; 84 (5)